PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) occurs in up to one-quarter of all critically ill adults receiving mechanical ventilation and is associated with high risk of death. In patients with ARDS, the volume of aerated lung is reduced substantially relative to healthy lung size due to alveolar edema and atelectasis. This smaller ?baby lung,? so-called for its reduced aerated volume available for ventilation, requires smaller tidal volume (Vt) than would be needed in healthy lungs to prevent regional overdistension. Low Vt ventilation limits ventilation- induced lung injury (VILI) and improves survival in patients with ARDS. Current standard of care involves scaling Vt to estimated healthy lung size, i.e. 6 mL/kg predicted body weight (PBW), and limiting end- inspiratory plateau airway pressure to ? 30 cmH2O. Yet, lung stress and strain vary considerably between ARDS patients receiving the same Vt per PBW due to individual differences in baby lung size and chest wall mechanics. Ideally, a precision medicine approach to Vt strategy in ARDS would account for these individual patient differences to better limit maximum lung distension at end-inspiration. By using esophageal manometry to estimate pleural pressure, one can measure at bedside the mechanical stress across the lung, independent of chest wall mechanics, as the transpulmonary pressure (lung stress = airway pressure ? pleural pressure). In a prior study, we found peak lung stress measured at end-inspiration was highly correlated with ?baby lung? volume (diseased lung size) but not Vt scaled to PBW (healthy lung size). Peak lung stress also independently predicted mortality in this cohort. This proposal seeks to (1) advance biological plausibility of peak lung stress as a bedside marker of ongoing VILI despite low Vt and (2) validate its prognostic utility for predicting patient- centered outcomes in ARDS. Our central hypothesis is that ARDS patients with higher peak lung stress experience more VILI and higher mortality despite low Vt ventilation. We will test this hypothesis via a secondary analysis of clinical, physiological, and biomarker data from the EPVent-2 Trial, a phase-II multicenter randomized trial of esophageal pressure-guided positive end-expiratory pressure (PEEP) titration in ARDS. Peak lung stress will be measured daily from respiratory physiological waveforms recorded in all trial participants. Plasma biomarkers for alveolar epithelial injury (sRAGE, surfactant protein-D) and systemic inflammation (IL-6, IL-8), as well as overt barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema), will be used as biological and clinical measures of VILI. Vital status and ventilator-free days will be used to determine prognostic utility of peak lung stress for predicting clinical outcomes in patients with ARDS. This research will elucidate mechanisms of occult VILI in patients receiving the current standard-of-care ?lung-protective? Vt strategy. Ultimately, results may inform development of novel strategies for individualizing Vt based on peak lung stress in effort to reduce morbidity and mortality from ARDS.